Novel Anti-bacterial Activities of β-defensin 1 in Human Platelets: Suppression of Pathogen Growth and Signaling of Neutrophil Extracellular Trap Formation

Human β-defensins (hBD) are antimicrobial peptides that curb microbial activity. Although hBD's are primarily expressed by epithelial cells, we show that human platelets express hBD-1 that has both predicted and novel antibacterial activities. We observed that activated platelets surround Staphylococcus aureus (S. aureus), forcing the pathogens into clusters that have a reduced growth rate compared to S. aureus alone. Given the microbicidal activity of β-defensins, we determined whether hBD family members were present in platelets and found mRNA and protein for hBD-1. We also established that hBD-1 protein resided in extragranular cytoplasmic compartments of platelets. Consistent with this localization pattern, agonists that elicit granular secretion by platelets did not readily induce hBD-1 release. Nevertheless, platelets released hBD-1 when they were stimulated by α-toxin, a S. aureus product that permeabilizes target cells. Platelet-derived hBD-1 significantly impaired the growth of clinical strains of S. aureus. hBD-1 also induced robust neutrophil extracellular trap (NET) formation by target polymorphonuclear leukocytes (PMNs), which is a novel antimicrobial function of β-defensins that was not previously identified. Taken together, these data demonstrate that hBD-1 is a previously-unrecognized component of platelets that displays classic antimicrobial activity and, in addition, signals PMNs to extrude DNA lattices that capture and kill bacteria

Physical and functional evidence in support of candidate chromosome 3p tumour suppressor genes implicated in epithelial ovarian cancer

Epithelial ovarian cancer (EOC) is difficult to detect in early stage disease, resulting in a high mortality rate. The molecular events underlying EOC development remain largely unknown. Chromosome 3 exhibits frequent deletions and rearrangements in EOC by cytogenetic analysis. In addition, loss of heterozygosity (LOH) mapping of matched ovarian tumour and constitutional DNA samples exhibits specific regions of chromosome 3 loss involving distinct regions: 3p25-p26, 3p24 and a region proximal to 3p14. Thus, chromosome 3p loss points to the location of tumour suppressor genes (TSG) implicated in tumourigenesis, based on Knudson's 'two-hit' model and the paradigm of the classical TSG. The dissertation hypothesis states at least one TSG implicated in EOC is located on chromosome 3p. A novel complementation approach based on the transfer of normal chromosome 3 fragments into OV-90, a tumourigenic EOC cell line harbouring LOH of the 3p arm, was used to generate functional evidence for chromosome 3p TSGs. Three hybrids exhibited complete suppression of tumourigenic potential based on the inability to form colonies in soft agarose, spheroids in cell culture, and tumours in nude mice xenograft models. While all hybrids had acquired various chromosome 3 regions, they all shared in common a 3p12-pcen interval, suggesting at least one common gene may have affected the suppression of tumourigenicity in the OV-90-derived hybrids. Twelve known/hypothetical genes mapping to 3p12-pcen region were characterized based on gene expression and mutation analysis following a classical model for TSG inactivation. To establish the relevance to EOC, gene expression of candidates was investigated in primary cultures of normal ovarian surface epithelial cells and both malignant serous and benign serous tumour samples. The gene expression and genetic analysis identified seven TSG candidates, none of which appeared to be mutated or transcriptionally silenced based on classical mechanisms of TSG inactivation in OV-90, thus suppression of tumourigenicity may have resulted from the functional complementation of one more haploinsufficient 3p12-pcen genes. Several genes (GBE1, VGLL3, ZNF654 ) appeared underexpressed in malignant tumours and these findings suggest the intriguing possibility that more than one 3p12-pcen gene was involved in the suppression of tumourigenicity in OV-90, and by extension, EOC

Self-Efficacy as a Relevant Construct in Understanding Sexual Response and Dysfunction

While self-efficacy has been widely used to explain and treat various biobehavioral responses, few investigations have examined this concept in the context of sexual response and dysfunction. In this study, the authors constructed a measure of sexual self-efficacy, investigated whether it differentiated men with and without sexual dysfunction, and determined the utility of this construct by exploring its relation to other variables known to be related to erectile dysfunction in a sample of 60 men with erectile dysfunction and 14 functional men visiting a urology clinic. The sexual self-efficacy index differentiated men with and without erectile dysfunction, and general linear modeling showed that the index did indeed relate to other variables known to affect sexual and emotional response during a partnered sexual experience. These findings suggest that, as a unifying construct that predicts cognitive, affective, motivational, and behavioral responses, sexual self-efficacy has the potential to play an important role in the assessment of effective treatments for sexual problems

CSI 2264: CHARACTERIZING YOUNG STARS IN NGC 2264 WITH STOCHASTICALLY VARYING LIGHT CURVES

We provide CoRoT and Spitzer light curves and other supporting data for 17 classical T Tauri stars in NGC 2264 whose CoRoT light curves exemplify the "stochastic" light curve class as defined in 2014 by Cody et al. The most probable physical mechanism to explain the optical variability within this light curve class is time-dependent mass accretion onto the stellar photosphere, producing transient hot spots. Where we have appropriate spectral data, we show that the veiling variability in these stars is consistent in both amplitude and timescale with the optical light curve morphology. The veiling variability is also well-correlated with the strength of the He i 6678 Å emission line, predicted by models to arise in accretion shocks on or near the stellar photosphere. Stars with accretion burst light curve morphology also have variable mass accretion. The stochastic and accretion burst light curves can both be explained by a simple model of randomly occurring flux bursts, with the stochastic light curve class having a higher frequency of lower amplitude events. Members of the stochastic light curve class have only moderate mass accretion rates. Their Hα profiles usually have blueshifted absorption features, probably originating in a disk wind. The lack of periodic signatures in the light curves suggests that little of the variability is due to long-lived hot spots rotating into or out of our line of sight; instead, the primary driver of the observed photometric variability is likely to be instabilities in the inner disk that lead to variable mass accretion

A large-scale binding and functional map of human RNA-binding proteins.

Many proteins regulate the expression of genes by binding to specific regions encoded in the genome1. Here we introduce a new data set of RNA elements in the human genome that are recognized by RNA-binding proteins (RBPs), generated as part of the Encyclopedia of DNA Elements (ENCODE) project phase III. This class of regulatory elements functions only when transcribed into RNA, as they serve as the binding sites for RBPs that control post-transcriptional processes such as splicing, cleavage and polyadenylation, and the editing, localization, stability and translation of mRNAs. We describe the mapping and characterization of RNA elements recognized by a large collection of human RBPs in K562 and HepG2 cells. Integrative analyses using five assays identify RBP binding sites on RNA and chromatin in vivo, the in vitro binding preferences of RBPs, the function of RBP binding sites and the subcellular localization of RBPs, producing 1,223 replicated data sets for 356 RBPs. We describe the spectrum of RBP binding throughout the transcriptome and the connections between these interactions and various aspects of RNA biology, including RNA stability, splicing regulation and RNA localization. These data expand the catalogue of functional elements encoded in the human genome by the addition of a large set of elements that function at the RNA level by interacting with RBPs